N-phenylamide and N-pyridylamide derivatives, method of preparing them and pharmaceutical compositions containing them

ABSTRACT

The present invention relates to the compounds of formula (I) in which X, R 1 , R 2 and R   3  are as defined in claim 1. These compounds are cholesteryl acyl transferase (ACAT) inhibitors.

The present invention relates to new N-phenyl-amide and N-pyridylamidederivatives, to the methods of preparing these compounds, to thepharmaceutical compositions containing them and to their use asmedicaments especially in the treatment of hyperlipidaemia andatherosclerosis.

It is known that lipid deposits, especially cholesterol deposits inblood vessels are responsible for the formation of atheroma plaqueswhich are the cause of a variety of cardiovascular diseases; moreprecisely, atheroma is a form of atherosclerosis characterized by anexcessive accumulation of lipids, in particular of cholesterol esters,in the wall of the vessels; it has recently been found that an enzyme,acyl Coenzyme A: Cholesteryl Acyl transferase (ACAT) is responsible forthe esterification of cholesterol, and a correlation was found betweenthe increase in the activity of this enzyme and the accumulation ofcholesterol esters in the vascular wall; it is also known that dietarycholesterol is absorbed in free form and is then esterified byintestinal ACAT for release into the bloodstream in the form of VLDL(very low density lipids) and/or of chylomicrons.

While several ACAT inhibitors have been identified (see for example: EP295 637, EP 415 413 or EP 497 201) the development of new ACATinhibitors having improved therapeutic properties should be continued.

Attempts have been made to develop ACAT-inhibiting products capable ofpreventing intestinal absorption of dietary and bile cholesterol and ofacting against the deposition of cholesterol esters in the wall of thevessels.

This search for ACAT inhibitors has led the inventors to develop a newfamily of N-phenylamide and N-pyridylamide derivatives and to find thatthese products manifest a potent vascular ACAT-inhibiting activityassociated with an intense antihyperlipidaemic effect on various animalspecies.

These properties of the compounds of the invention make themparticularly useful especially for the treatment of hyperlipidaemia andof athero-sclerosis.

The compounds of the invention have, more precisely, the formula:

in which X is O, S or CH₂;

R₁ and R₂, which may be identical or different, are hydrogen,(C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or alternatively R₁ and R₂, togetherwith the carbon atom bearing them, form (C₃-C₈)cycloalkyl;

R₃ is a (C₆-C₁₂)aryl optionally substituted with one or more Y radicals,which may be identical or different; or a 5- to 7-membered heteroarylcomprising 1 to 3 endocyclic heteroatoms chosen from O, S and N which isoptionally substituted with one or more Y radicals, which may beidentical or different;

Y is halogen, a (C₁-C₆)alkyl optionally substituted with one or morehalogens, a (C₁-C₆)alkoxy optionally substituted with one or morehalogens, a (C₁-C₆)alkylthio optionally substituted with one or morehalogens, (C₁-C₇)acylamino, (C₁-C₃)acyloxy, hydroxyl, nitro, cyano,amino, (C₁-C₆)alkylamino, di-(C₁-C₆)-alkylamino, pyrrolidono,piperidino, morpholino, (C₁-C₄) alkylsulfonylamino, (C₂-C₅)alkoxycarbonyl, carboxyl, (C₂-C₆)alkylcarbonyl, carbamoyl,(C₂-C₅)alkylcarbamoyl, di-(C₂-C₅)aalkylcarbamoyl or(C₁-C₆)alkylsulfonyl;

R₄ and R₅, which may be identical or different, are a Y radical oralternatively a hydrogen atom;

Ar is one of the following groups A, B or C:

T₁ and T₂, which may be identical or different, are halogen,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio or (C₁-C₆) alkyl;

T is a hydrogen atom or (C₁-C₆) alkyl;

T₃ and T₄, which may be identical or different, are (C₁-C₆) alkyl,(C₁-C₆) alkoxy, (C₁-C₆) alkylthio, (C₆-C₁₂)arylthio,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl-carbonyl, (C₆-C₁₂)arylcarbonyl or—(CH₂)_(p)—OR in which p is 1, 2, 3 or 4 and R is (C₂-C₃)alkyl,

R₆ and R₇ are each a hydrogen atom or alternatively

R₆ and R₇ together are a bond;

z is either

(i) the divalent group —CHR₉— in which R₉ is a hydrogen atom or(C₁-C₆)alkyl;

or (ii) the divalent group —CHR₁₀—CHR₁₁— in which R₁₀ and R₁₁ togetherform a bond such that Z is —CH═CH—or alternatively R₁₀ and R₁₁, whichmay be identical or different, are as defined above for R₉;

or (iii) the divalent group —CHR₁₂—CHR₁₃—CH₂— in which R₁₂ and R₁₃together form a bond such that Z is —CH═CH—CH₁₂—, or alternatively R₁₂and R₁₃, which may be identical or different, are as defined above forR₉, as well as their addition salts with a pharmaceutically acceptableacid or base.

The addition salts of these compounds with pharmaceutically acceptableacids or bases also form part of the invention. Examples of these saltsare the salts formed from hydrochloric acid, p-toluenesulfonic acid,fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid,hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acidand mandelic acid.

In some cases, the compounds of the invention have one or more chiralcentres. It should be understood that each stereoisomer forms part ofthe invention.

(C₁-C₆)Alkyl is a linear or branched, saturated hydrocarbon radical of 1to 6 carbon atoms. The (C₁-C₆)alkoxy group consequently is the alkyl-O—group and the (C₁-C₆)alkylthio group is the alkyl-S— group where alkylis as defined above.

Moreover, (C₃-C₈)cycloalkyl is understood to mean a saturated mono- orbicyclic hydrocarbon radical comprising from 3 to 8 carbon atoms.Examples are cyclopropyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term (C₆-C₁₂)aryl is, moreover, a mono- or polycyclic aromatic grouphaving 6 to 12 carbon atoms, such as phenyl, naphthyl or anthryl. Thus,(C₆-C₁₂)arylthio is the (C₆-C₁₂)-aryl-S— radical.

As a 5- to 7-membered heterocycle comprising 1 to 3 endocyclicheteroatoms chosen from O, S and N, there may be mentioned furan,thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.

The halogen atoms are chlorine, bromine, fluorine and iodine.

The term acyl is the alkylcarbonyl radical. Thus, (C₁-C₇)acylamino is(C₁-C₇)alkylcarbonylamino and (C₁-C₃)acyloxy is (C₁-C₃)alkylcarbonyloxy.

Among these compounds, there are 6 subgroups of preferred compounds.

A first subgroup consists of compounds of formula I in which Y ishalogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy or trifluoromethyl.

A second subgroup comprises the compounds of formula I in which:

R₁ and R₂, which may be identical or different, are hydrogen oralternatively R₁ and R₂, together with the carbon atom bearing them,form (C₃-C₈)cycloalkyl;

R₃ is a (C₆-C₁₂)aryl optionally substituted with one or more Y radicals,which may be identical or different;

Y is halogen;

R₄ and R₅ are each a hydrogen atom;

Ar is one of the following groups A, B or C:

T₁ and T₂, which may be identical or different, are (C₁-C₆) alkyl;

T is a hydrogen atom or (C₁-C₆)alkyl;

T₃ and T₄, which may be identical or different, are (C₁-C₆)alkyl;(C₁-C₆)alkoxy or (C₁-C₆)alkylthio;

R₆ and R₇ are each a hydrogen atom or alternatively R₆ and R₇ togetherare a bond;

Z is either

(i) the divalent group —CHR₉— in which R₉ is a hydrogen atom or(C₁-C₆)alkyl; or

(ii) the divalent group —CHR₁₀—CHR₁₁— in which R₁₀ and R₁₁ together forma bond such that Z is —CH═CH—, or alternatively R₁₀ and R₁₁ are each ahydrogen atom.

A third subgroup consists of the compounds of formula I in which Z is—CHR₁₂—CHR₁₃—CH₂—, R₁₂ and R₁₃ being as defined above.

Among the compounds of the first, second and third subgroups definedabove, those for which R₁ and R₂ are a hydrogen atom are moreparticularly preferred.

A fourth subgroup consists of the compounds of formula I in which X is Oor S and R₁ and R₂, together with the carbon atom bearing them, form a(C₃-C₈) cycloalkyl.

A fifth subgroup of preferred compounds comprises the compounds offormula I in which X is O or S and Z is —CH═CH— or alternatively—CH═CH—CH₂.

In general, it is preferable that Ar is2,4-dimethylthio-6-methyl-3-pyridyl; 2-methoxy-4-hexylthio-3-pyridyl and2,6-diisopropylphenyl.

A sixth subgroup consists of the compounds of formula I in which X isCH₂.

Among these compounds, those for which Ar is a group B or C are moreparticularly preferred. Here again, the meanings2,4-dimethylthio-6-methyl-3-pyridyl and 2-methoxy-4-hexylthio-3-pyridylfor Ar are particularly advantageous.

According to a preferred embodiment of the invention, R₃ is preferablyphenyl which is optionally substituted, pyridyl or thienyl which isoptionally substituted, such as for example 2-pyridyl or 2-thienyl whichis optionally substituted at the 5-position.

The compounds of the invention may be prepared by coupling an acid offormula II

in which R₁, R₂, R₃, R₄, R₅, R₆, R₇ and Z are as defined in claim 1,with an aromatic amine of formula III:

Ar—NH₂  (III)

in which Ar is as defined above.

This method, as well as the preferred variants of this method which aredescribed below, are a subject of the invention.

The coupling of the acid of formula II with the amine of formula III maybe simply carried out by reacting the amine of formula III with anactivated derivative of the acid of formula II such as an acid chloride,an ester or a mixed anhydride.

More precisely, persons skilled in the art know that they can envisagethe amination of the following activated acid derivatives: P_(o)—CO—SH,P_(o)—CO—SR, P_(o)—CO—Se—Me, P_(o)—CO—B(OR)₂, (P_(o)—COO)₄Si, P_(o)—CO—C(hal)₃ or P_(o)—CO—-N₃ in which

P_(o) is:

hal is a halogen atom, and

R is (C₁-C₆)alkyl.

The methods of activating organic acids are known in the art.

Moreover, the coupling of the acid of formula II with the amine III maybe carried out using any of the techniques used in liquid-phase peptidesynthesis.

These techniques are, for example, described in “Methods of PeptideSynthesis” T. Wieland and H.

Determann, Angew. Chem. Interm. Ed. Engl., 2, 358, (1963).

By way of example, the chlorides of the acid of formula II may beobtained by the action of SOCl₂, oxalyl chloride, PCl₃ or PCl₅.

It is also possible to prepare an acid chloride by the action oftriphenylphosphine, in carbon tetrachloride, on the acid of formula II.

For the preparation of an acid bromide, the corresponding brominatedreagents, such as oxalyl bromide, PBr₃ or PBr₅, may be used.

As an example of preparation of a mixed anhydride, there may bementioned the action of bis(2-oxo-3-oxazolidinyl)phosphinic acid on theacid of formula II. This reaction is preferably carried out in thepresence of a base as in the majority of activating reactions. This basemay be either pyridine, ethylenediamine or 4-dimethylaminopyridine.

Thus, according to a preferred embodiment of the invention, thecompounds of formula I are prepared:

using the following steps (i) and (ii):

(i) an acid of formula II is treated with oxalyl chloride in thepresence of dimethylformamide; and then

(ii) an amine of formula III is reacted with the compound obtained instep (i);

or alternatively

using the following steps (i) and (ii):

(i) an acid of formula II is treated withbis(2-oxo-3-oxazolidinyl)phosphinic acid in the presence of a base; andthen

(ii) an amine of formula III is reacted with the compound obtained instep (i).

The following two operating protocols can for example be used forcoupling the acid II with the amine III.

Method A:

According to this method, the acid of formula II is activated in theform of an acid chloride before being coupled to the amine III.

The reaction of oxalyl chloride with the acid of formula II is carriedout in an apolar aprotic solvent such as a hydrocarbon, for example ahalogenated hydrocarbon.

The oxalyl chloride and a catalytic quantity of dimethylformamide areadded to a solution of the compound of formula II, kept at a temperatureof between 15 and 25° C. and preferably at room temperature. Thereaction medium is then heated to a temperature of between 30 and 70°C., for example the reflux temperature of the solvent used. The reactionis monitored by thin-layer chromatography. The solvent is thenevaporated and the residue is taken up in an apolar aprotic solvent suchas, for example, the halogenated hydrocarbon previously used, beforebeing supplemented with the aromatic amine III and with a base such aspyridine or 4-dimethylaminopyridine. This reaction is continued for thelength of time necessary at a temperature of between 15 and 85° C.,preferably at room temperature.

Method B:

According to this method, the acid of formula II is activated in theform of a mixed anhydride before being coupled to the amine III.

A weak base such as triethylamine is added to a solution of the acid offormula II in an apolar aprotic solvent such as a halogenatedhydrocarbon, and then the reaction medium is heated to a temperature ofbetween −10 and 10° C., preferably between 0 and 5° C.Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride is then added. Whenthe reaction is complete, the aromatic amine of formula III is added tothe reaction medium all at once, the latter being kept between −10 and10° C. (preferably between 0 and 5° C.). A base in solution in an apolaraprotic solvent such as a halogenated hydrocarbon is then introduced insmall portions to the reaction medium.

The compound of formula I obtained is then isolated and purified.

The amines of formula III are either directly available commercially, orare easily available from commercial products.

In the remainder of the text, methods of preparing the compounds offormula II are provided.

The compounds of formula II in which Z is —CHR₉— may be obtained byfollowing the reaction scheme A.

The first step allows the introduction of the carboxaldehyde functionalgroup.

A compound of formula VIII in which R₁, R₂, R₃, R₄ and R₅ and X are asdefined above is reacted with phosphorus oxychloride. This reactiontakes place in a preferably polar aprotic solvent such asdimethylformamide (DMF). The reaction temperature varies between −20° C.and room temperature. Preferably, the reaction is carried out between 0°C. and 5° C. and its progress is monitored by thin-layer chromatography.The aldehyde VII obtained is isolated in the usual manner by dilution ofthe reaction medium in a water-ice mixture, neutralization and thenextraction and purification.

The next step of reduction of the aldehyde functional group to ahydroxymethyl functional group is carried out using any of the methodsknown in the art, as long the reaction conditions are such that they donot cause undesirable side reactions. Where appropriate, the reactivefunctional groups of the groups R₁, R₂, R₃, R₄ and R₅ are protected.

Among the reagents commonly used to this end, there may be mentionedlithium aluminum hydride, sodium borohydride or sodium cyanoborohydride.When sodium borohydride is used, the reaction is preferably carried outin a methanol-water mixture at a temperature of between −40 and 0° C.,better still between −25 and −15° C. Here again, the compound obtainedis isolated in a manner known per se.

The alcohol of formula VI thus isolated is then converted to thecorresponding alkyl chloride. This conversion may be carried out in anymanner, as long as the reaction conditions are such that they do notcause side reactions. Where appropriate, the reactive functional groupsof the groups R₁, R₂, R₃, R₄ and R₅ are protected.

A known method consists in treating the alcohol VI with thionyl chloridein an inert solvent such as, for example, a toluene- or benzene-typearomatic hydrocarbon, at a temperature of between 15 and 30° C.,preferably at room temperature.

Other reagents may be used for the chlorination of the compound VI suchas, for example, PCl₅, PCl₃ or POCl₃.

The chlorinated compound of formula V is then treated with an alkalimetal cyanide (MCN) such as sodium cyanide in a polar aprotic solventsuch as DMF. The reaction temperature is kept between 0 and 50° C.depending on the reactivity of the chloride V. When MCN is sodiumcyanide, a temperature of between 20 and 25° C. is generally suitable.The compound of formula IV obtained is isolated and purified in aconventional manner.

The compounds of formula II in which R₉ is hydrogen are easily preparedfrom the nitrile IV by acidic or basic treatment. To this end, thefollowing reagent systems may be used:

NaOH/H₂O₂ or NaOHaq

H₂SO₄

HCOOH/HBr or HCl

AcOH/BF₃

AcOH/HCl.

For example, the nitrile IV may be hydrolysed using an AcOH/HCl: 40/60to 60/40 mixture, a 1/1 mixture being perfectly appropriate. In thiscase, the AcOH/HCl mixture preferably plays the role of solvent, thetemperature being unimportant between 0 and 50° C., preferably between15 and 25° C.

In order to obtain the compounds of formula I in which R₉ is(C₁-C₆)alkyl, the corresponding compound of formula II in which R₉ is ahydrogen atom is treated with an alkyl halide of formula R₉-X in which Xis a halogen atom, a group (C₁-C₆)alkylsulfonyloxy or(C₆-C₁₀)arylsulfonyloxy optionally substituted with (C₁-C₆)alkyl, and R₉is (C₁-C₆)alkyl, in the presence of a strong base capable of removingthe hydrogen at the α position with respect to the carboxyl functionalgroup in the compound of formula II (R₉=H). Such a base is, for example,lithium diisopropylamide (LDA).

According to a preferred embodiment, LDA is prepared in situ fromn-butyllithium and diisopropylamine at a temperature of between −15 and5° C., preferably at about 0° C. The solvent used for the generation ofLDA is a polar aprotic solvent such as tetrahydrofuran. The halide R₉-Xand the compound of formula II are then added to the reaction medium.The reaction temperature is, for example, a temperature of between 15and 35° C., preferably a temperature of between 20 and 25° C.

When the compound of formula I is such that Z is —CHR₁₀—CHR₁₁—, it maybe prepared according to reaction scheme B.

The introduction of a bromine atom into the compound of formula VIII isobtained by the action of N-bromosuccinimide (NBS) on the compound offormula VIII dissolved in a polar aprotic solvent such asdimethylformamide in the absence of moisture. The reaction temperatureis for example room temperature. It may nevertheless vary, depending onthe reactivity of the compound of formula VIII, between 10 and 35° C.

The next step consists in converting the brominated derivative obtainedof formula IX to a compound of formula X. To do this, an alkyl acrylateof formula H₂C═CH—COOR in which R=(C₁-C₆)alkyl is reacted with thebrominated derivative IX in the presence of palladium acetate, aphosphine and a base. The reaction advantageously takes place in a polaraprotic solvent such as dimethylformamide.

The base may be triethylamine, pyridine or 4-dimethylaminopyridine,preferably triethylamine.

The phosphine for example has the formula PAr′₃ in which Ar′ ispreferably a C₆-C₁₂aryl optionally substituted with a (C₁-C₆)alkyl.PAr′₃ is for example triphenylphosphine or tritolylphosphine.

For the reaction to progress well, the compound of formula IX, dissolvedin DMF, the base, the phosphine and the palladium acetate are firstbrought into contact, then the acrylate of formula CH₂═CH—COOR is addedto the reaction medium.

The resulting ester of formula X is isolated in a conventional mannerand then saponified in a manner known per se to give a compound offormula II in which R₁₀ and R₁₁ together form a bond.

Starting with this compound, it is possible to easily have access to allthe compounds of formula II in which Z is —CHR₉—CHR₁₀—.

For example, the acid of formula II obtained above:

is subjected to a catalytic hydrogenation. By judiciously controllingthe hydrogenation conditions, there is obtained either a compound offormula II in which R₆, R₇, R₁₀ and R₁₁ are each a hydrogen atom, or acompound of formula II in which R₆ and R₇ together form a bond and R₁₀and R₁₁ are each a hydrogen atom.

The compounds of formula II in which Z is —CHR₁₂—CHR₁₃—CH₂— may beobtained using a Wittig reaction starting with the aldehyde of formulaVII (Scheme A). It is for example possible to use a reagent systemcomposed (i) of a phosphonium halide of formula ROOC—CH₂—CH₂—P⁺A³, halein which R is hydrogen or (C₁-C₆)alkyl, hal is halogen and A is chosenfrom a (C₆C₁₂)aryl optionally substituted with (C₁-C₆)alkyl and (ii) ofa base such as an alkali metal tert-butoxide (tBuOK), an alkali metalhydride (NaH) or an alkyl-lithium (C₄H₉Li). The reaction mayadvantageously be carried out in a polar aprotic solvent such asdimethylformamide or tetrahydrofuran at a temperature of between 0 and30° C.

According to another of its aspects, the invention relates to apharmaceutical composition comprising at least one compound of formulaI, in combination with one or more pharmaceutically acceptable vehicles.

The vehicles which may be used are, for example, fillers, diluents,binders, wetting agents, disintegrating agents, surface-active agents,and lubricants. The pharmaceutical composition may be in any desirableunit form, including tablets, pills, powders, liquids, suspensions,emulsions, granules, capsules, suppositories, injections (solutions andsuspensions) and the like.

To prepare tablets, it is possible to use vehicles known in this field,for example excipients, such as lactose, sucrose, sodium chloride,glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose,silicic acid and the like; binding agents, such as water, ethanol,propanol, a simple syrup, a glucose solution, a starch solution, agelatin solution, carboxymethylcellulose, gum lac, methyl cellulose,potassium phosphate or polyvinylpyrrolidone and the like; disintegratingagents, such as dried starch, sodium alginate, agar powder, laminariapowder, sodium bicarbonate, calcium carbonate, fatty acid esters ofpolyoxyethylenesorbitan, sodium lauryl sulfate, a stearic acidmonoglyceride, starch, lactose and the like; disintegration inhibitors,such as refined sugar, stearin, cocoa butter, hydrogenated oils and thelike; absorption accelerators, such as a quaternary ammonium base,sodium lauryl sulfate and the like, wetting agents, such as glycerin,starch and the like; adsorbing agents, such as starch, lactose, kaolin,bentonite, colloidal silicic acid and the like; a lubricating agent suchas purified talc, salts of stearic acid, powdered boric acid,polyethylene glycol and the like.

In the case of the preparation of tablets, the tablets may, moreover, becoated with a customary coating material so as to be converted tosugar-coated tablets, tablets coated with a gelatin film, tabletsbearing enteric coatings, film-coated tablets, or tablets with a doublelayer or with multiple layers.

To form into pills, it is possible to use, for example, known vehicleswhich are commonly used in this field, such as excipients such asglucose, lactose, starch, cocoa butter, hydrogenated vegetable oils,kaolin or talc and the like; binders, such as powdered gum arabic,powdered gum tragacanth, gelatin, ethanol and the like; anddisintegrating agents, such as laminaria powder, agar and the like.

To form suppositories, it is possible to use known vehicles which arewidely used in this field, for example polyethylene glycols, cocoabutter, higher alcohols, higher alcohol esters, gelatin, semi-syntheticglycerides and the like.

To produce injectable preparations, solutions and suspensions aresterilized and they are preferably made isotonic with respect to blood.To produce injectable preparations, it is also possible to use vehicleswhich are commonly used in this field, for example water, ethyl alcohol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol, fatty acid esters of polyoxyethylenesorbitan and thelike. In this case, an appropriate quantity of sodium chloride, glucoseor glycerin may be added to the desirable pharmaceutical preparations inorder to make the solution isotonic. Furthermore, it is possible to addto the desirable pharmaceutical preparations, where appropriate,dissolving agents, buffer solutions, analgesic agents which arecustomarily used, as well as colouring agents, preservatives, perfumes,taste-modifying agents, sweetening agents and other medicaments.

The compounds of the invention have proved to be potent inhibitors ofacyl-coenzyme A. As such, they are useful in the treatment or theprophylaxis of hypercholesterolaemia, atheromatous atherosclerosis andcan even prevent possible ischaemic accidents such as, for example, amyocardial infarction as well as cerebrovascular diseases.

The pharmacological properties of the invention compounds weredemonstrated by the following tests.

Test A: measurement of in vitro hepatic ACAT inhibition in rats: maleWistar rats weighing 220-250 g were sacrificed by cervical dislocation;the liver was removed and homogerused to prepare the microsomal fractionby ultracentrifugation; these microsomes were incubated with ¹⁴C-oleylcoenzyme A according to the method described by P. J. GILLIES et al.,Exp. and Mol. Pathol. 1986, 44, 329-339; lipids were extracted from theincubate with a methanol-chloroforme mixture and ¹⁴C-oleyl cholesterolwas separated by TLC; the latter represented the measurement of the ACATactivity and the results were expressed in inhibitory concentration 50(IC₅₀) representing the concentration of compound inhibiting the ACATactivity by 50%.

As an example, the IC₅₀ values of compounds No. 1, 4 and 6 wererespectively 94×10⁻⁹ mole/l, 74×10⁻⁹ mole/l and 31×10⁻⁹ mole/l.

Test B: measurement of intestinal absorption of cholesterol in rats;male Wistar rats weighing 230-250 g and fasted for 24 hours receivedsimultaneously the test substance per os and triton WR 1339 by IV route;one hour later, they were again treated orally with ³H-cholesterol;three hours later, I ml of blood was taken from the retro-orbital sinus:the blood radioactivity determined on 0.1 ml of serum represented themeasurement of the absorption of ³H-cholesterol. The results wereexpressed in effective dose 50 (ED₅₀) in mg per kg of animal andrepresented the quantity of compound inhibiting the intestinalabsorption of cholesterol by 50%.

As an example, the ED₅₀ values of compounds No. 1, 4 and 6 wererespectively 0.005 mg/kg, 0.038 mg/kg and 0.023 mg/kg.

Test C: hypercholesterolemia model; claim 1 compounds were tested byoral route in animals subjected to a cholesterol-rich diet;

As an example, in the male Wistar rat fed a 2.5% cholesterol enricheddiet for 8 days and treated for 2 days with compound No. 1, totalcholesterol was lowered by 50% at the dose of 0.78 mg/kg; the effect wasmainly observed on VLDL (Very Low Density Lipid).

As an example, in the rabbit fed a 0.5% cholesterol enriched diet for 15days and treated sumultaneously with compound No. 1, total cholesterolwas decreased by 70% at the dose of 0.1 mg/kg; the effect was mainlyobserved on VLDL (Very Low Density Lipid).

The following examples are given by way of illustration as preferredembodiments.

I—Preparation of Aromatic Amines of Formula III

When Ar is 2-(C₁-C₆)alkoxy-4-n-hexylthio-3-pyridyl, the reaction schemefollowed is, for example, the following:

Step 1

Tert-Butyl (2-methoxy-3-pyridyl) carbamate:

3.72 g (30 mmol) of 2-methoxy-3-pyridylamine in solution in 30 ml oftetrahydrofuran are placed in a 100-ml reactor, protected from moisture,and under a nitrogen atmosphere, and then 60 ml (60 mmol) of sodiumbis(trimethylsilyl)amide in a 1 M solution in tetrahydrofuran are addeddropwise at room temperature.

After stirring the reaction mixture for 20 minutes at room temperature,6.54 g (30 mmol) of di-tert-butyl carbonate are added dropwise to thereaction medium kept at room temperature.

After stirring at room temperature for 3 hours, the tetrahydrofuran isevaporated off. The residue is taken up in ethyl acetate, washed withwater, with hydrochloric acid (0.1 M) and then with water (until a pH ofthe washings equal to 7 is obtained). After drying the organic phaseover sodium sulfate, and evaporation of the solvent, a black oil isobtained which is chromatographed on a silica gel (eluent ethylacetate-hexane: 1-3). After evaporation of the solvent, 6.1 g of anamber-coloured oil are obtained, that is to say a yield of 90.2%.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-2); Rf=0.4 I.R.:υ NH=3425, CO=1731; NMR: (CDCl₃): 1.5 (s, 9H); 3.95 (s, 3H); 6.8 (dd,1H, J=5 Hz, J=7.8 Hz); 6.9 (s, 1H); 7.7 (dd, 1H, J=5 Hz, J=1.6 Hz); 8.2(d, 1H, J=7.8 Hz).

Step 2

Tert-Butyl (4-n-hexylthio-2-methoxy-3-pyridyl) carbamate:

4.48 g (20 mmol) of the compound obtained in the preceding step insolution in 100 ml of diethyl ether and 9.05 ml (60 mmol) oftetramethylethylene-diamine are placed in a reactor, protected frommoisture, and under a nitrogen atmosphere.

After having cooled the solution to −70° C., 37.5 ml (60 mmol) ofn-butyllithium in hexane (1.6 M) are added dropwise. The reaction mediumis stirred for 2 hours at −10° C. and then 14.1 g (60 mmol) of dihexylsulfide are added dropwise at −70° C.

After stirring the solution for 12 hours at room temperature, thereaction medium is taken up in water and extracted with diethyl ether.The organic phase is washed with hydrochloric acid (0.1 M) and then withwater until a pH of the washings equal to 7 is obtained, and thenfinally dried over sodium sulfate. After evaporation of the solvent, anoil is obtained which is chromatographed on a silica gel (eluent ethylacetate-hexane: 1-5). After evaporation of the solvent, 5.6 g of an oilis obtained which crystallizes, that is to say a yield of 82.3%. Itsmelting point is between 72 and 74° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-3); Rf=0.3 I.R.:υ NH=3171, CO=1720; NMR: (CDCl₃): 0.85 (t, 3H); 1.3 (m, 4H); 1.45 (m,11H); 1.7-1.8 (m, 2H); 3.0 (t, 2H); 4.25 (s, 3H); 6.7 (d, 1H, J=6.8 Hz);7.85 (d, 1H, J=6.8 Hz).

Step 3

4-n-Hexylthio-2-methoxy-3-aminopyridine

5.6 g (16.45 mmol) of the compound obtained in the preceding step insolution in 140 ml of ethyl acetate and 140 ml of a 4 M hydrochloricacid solution are mixed, with vigorous stirring, in a 500-ml reactor.

The reaction medium is left for 12 hours at room temperature. Thereaction medium is then neutralized with sodium bicarbonate (until a pHof the washings equal to 7 is obtained), then the organic phase iswashed with water and dried over sodium sulfate and then evaporated off.The oil obtained is chromatographed on a silica gel (eluent:dichloro-methane). After evaporation of the solvent, 3.63 g of an oilare obtained, that is to say a yield of 91.8%.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-3); Rf=0.6; NMR:(CDC₃): 0.85 (t, 3H); 1.2-1.3 (m, 4H) 1.3-1.4 (m, 2H); 1.5-1.6 (m, 2H);2.85 (t, 2H); 3.95 (s, 3H); 4.1 (s, 2H); 6.7 (d, 1H, J=6.7 Hz); 7.4 (d,1H, J=6.7 Hz).

II—Preparation of the Carboxylic Acids of Formula II in Which Z is—CHR₁₀—CHR₁₁

1—3-[Spiro{cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-3′-benzopyranyl)}]propanoicacid

Step 1

Spiro{cyclopentane-1,2′-(3′-bromo-4′-(4-fluorophenyl)-2′H-benzopyran))

43.4 g (0.3 mol) of N-bromosuccinimide in solution in 500 ml ofdimethylformamide are placed in a reactor kept protected from moisture.A solution of 70.1 g (0.25 mol) ofspiro{cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-benzopyran} in solutionin one litre of dimethylformamide is added dropwise to this solutionkept at room temperature. The solution is stirred overnight at roomtemperature and then poured into 3 litres of ice-cold water. Thereaction medium is extracted with diethyl ether. The organic solution isthen washed with water (until a pH of the washings equal to 7 isobtained), and then dried over sodium sulfate. After evaporation of thesolvent, the solid obtained is dispersed in 100 ml of ethanol, placed at−20° C. for 12 hours, and then drained and dried. 68.7 g of the expectedproduct are thus obtained, that is to say a yield of 76.5%. This producthas a melting point of between 107 and 109° C. (ethanol).

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 2-100); Rf=0.7.

Step 2

Ethyl3-{spiro[cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-3′-benzopyranyl)]}-prop-2-enoate.

14.1 g (39.25 mmol) of the compound obtained in the preceding step insolution in 40 ml of dimethylformamide are placed in a reactor keptprotected from moisture. A solution of 90 ml of triethylamine insolution in 90 ml of dimethylformamide is added dropwise to thissolution, kept at room temperature, and then the following reagents areadded successively to the reaction medium:

0.72 g (2.3 mmol) of tri(2-tolyl)phosphine;

0.18 g (0.79 mmol) of palladium acetate, and then dropwise at roomtemperature,

19.55 ml of ethyl acrylate (180.5 mmol).

The reaction medium is then heated under reflux (95° C.) for 2 hours.The reaction medium is then poured over a water/ice mixture and thenacidified with a concentrated hydrochloric acid solution of pH equalto 1. The precipitate obtained is extracted with methylene chloride, andthen the organic solution is washed with water (until a pH of thewashings equal to 7 is obtained), dried over sodium sulfate andevaporated off.

The solid obtained is finally dispersed in 100 ml of ethanol and thendrained. 10.5 g of the expected compound are obtained, that is to say ayield of 70.8%. The compound obtained has a melting point of between 138and 140° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 5-95); Rf=0.3;I.R.: υ C.O=1715 cm⁻¹.

Step 3

3-(Spiro[cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-3′-benzopyranyl)]}-prop-2-enoicacid.

18.92 g (50 mmol) of the compound obtained in the preceding step arepoured into 700 ml of ethanol. 75 ml (75 mmol) of 1 N sodium hydroxideare added to this solution. The reaction medium is then heated underreflux for 40 minutes. After evaporation, the solid obtained isdispersed in diethyl ether and drained. The solid is redissolved inwater, the insoluble portion being filtered. The aqueous phase isacidified with hydrochloric acid (to pH=1), and then extracted withethyl acetate. The organic phase is washed with water (until a pH of thewashings equal to 7 is obtained), dried and evaporated off.

The solid obtained is dispersed in pentane and drained.

17.5 g of the expected product are obtained, that is to say a yield of100%. This product has a melting point of between 172 and 174° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1—1); Rf=0.46;I.R.: υ C.O=1682 cm⁻¹; NMR: (CDCl₃): 1.5-2.5 (m, 8H); 5.5-5.8 (d, 1H)6.5-7.5 (m, 9H); 10 (s, 1H). Percentage analysis: C₂₂H₁₉FO₃, 0.25 molH₂O MW: 354.87.

C H N Calculated % 74.39 5.49 5.35 Found % 74.65 5.58 5.39

Step 4

3-[Spiro{cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-3′-benzopyranyl)}]propanoicacid

A solution composed of 7 g (20 mmol) of the acid obtained in thepreceding step, 170 ml of tetrahydrofuran and 5 g of Raney nickel areheated, with stirring, for 2 hours 30 minutes in an autoclave at ahydrogen pressure of 100 bar, at 60° C. After filtration of the catalystand evaporation of the solvent, the solid residue is dispersed in hexaneand drained. This compound has a melting point of 177° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-1); Rf=0.60;I.R.: υ C.O=1706 cm⁻¹;

2—Other acids of formula II in which Z is —CHR₁₀—CHR₁₁—, and theircorresponding precursor esters

By following the operating protocol described above (II.1) in the caseof3-[spiro{cyclopentane-1,2′-(4′-(4-fluorophenyl)-2′H-3′-benzopyranyl)}]propanoicacid, the following acids of formula II were obtained.

TABLE 1

Prep- ara- Melting tion point No. X R₁₀ R₁₁ R₃ R R₁ R₂ (° C.) I.2.1 O HH 4-F—C₆H₄ H —(CH₂)₄— 177 I.2.2 S H H C₆H₅ H H H oil I.2.3 O bond4-F—C₆H₄ C₂H₅ —(CH₂)₄— 138-140 I.2.4 O bond 4-F—C₆H₄ H —(CH₂)₄— 172-174I.2.5 S bond C₆H₅ C₂H₅ H H oil I.2.6 S bond C₆H₅ H H H oil I.2.7 O bondC₆H₅ C₂H₅ H H oil I.2.8 O bond C₆H₅ H H H 216-218

In Table 1 above, the term “bond” means that R₁₀+R₁₁ together form abond and 4-F-C₆H₄ is the radical of formula

Table 2 assembles the intermediate bromides which led to the compoundsof Table 1 above.

TABLE 2

Intermediate Melting No. X R₁ R₂ R₃ point (° C.) IX. 1 O —(CH₂)₄4-F—C₆H₄— 107-109 IX. 2 S H H C₆H₅— oil IX. 3 O H H C₆H₅— oil

III—Preparation of the Carboxylic Acids of Formula II in Which Z is—CHR₉—

1—2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetic acid

Step 1

4-Phenyl-2H-3-benzo[b]pyranylcarboxaldehyde.

3.13 litres (40.7 mol) of dimethylformamide are placed in a ⁶-litrereactor, kept protected from moisture and under a nitrogen atmosphere.748 ml (8.14 mol) of phosphorus oxychloride are added dropwise to thissolution, kept between 0 and 5° C. The reaction medium is stirred at 5°C. for 20 minutes, and then 175.28 g (0.814 mol) of4-phenyl-2H-benzo[b]pyran dissolved in 246 ml of dimethylformamide areadded to this solution. The solution is stirred for 48 hours at roomtemperature. The reaction medium is then poured into an ice-watermixture, neutralized with a concentrated sodium hydroxide solutionhaving a pH greater than 10 and stirred for 1 hour at room temperature.The medium is then extracted three times with diethyl ether.

The organic solution is then washed with water and dried over sodiumsulfate. After evaporation, an oil is obtained which is dispersed in 200ml of heptane. This solution is allowed to stand for 1 hour at −20° C.and then the solid formed is filtered and it is dried. 144.5 g of theexpected product are obtained, that is to say a yield of 75.1%. Thiscompound has a melting point of between 78 and 80° C.

TLC: (MERCK “Kieselgel 60” silica gel; CH₂Cl₂-hexane: 1-1); Rf=0.5; NMR:(CDCl₃): 5.15 (s, 2H); 6.9-7.5 (m, 9H); 9.45 (s, 1H); I.R.: υ CO=1660cm⁻¹.

Step 2

(4-Phenyl-2H-3-benzo[b]pyranyl)methanol.

302.6 g (1.28 mol) of the compound obtained in the preceding step insolution in a mixture of 7.7 litres of methanol and 260 ml of water areplaced in a 20-litre reactor kept under a nitrogen atmosphere. 53.3 g(1.4088 mol) of sodium borohydride are added in small portions to thissolution kept at room temperature. At the end of the addition, thereaction medium is stirred for 30 minutes. After evaporation of thesolvent, the residue is dissolved in diethyl ether and the organicsolution is washed with water until a pH of the washings equal to 7 isobtained. After evaporation of the solvent, an oil is obtained which iscrystallized from 200 ml of pentane. After 2 hours at −20° C., the solidobtained is drained. 269.3 g of the expected product are thus obtained,that is to say a yield of 88.3%. The melting point of this compound isbetween 67 and 68° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-1); Rf=0.5; I.R.:υ CO=3356 cm⁻¹.

Step 3

3-(Chloromethyl)-4-phenyl-2H-benzo[b]pyran.

269.3 g (1.13 mol) of the compound obtained in the preceding step insolution in 2.7 litres of toluene are placed in a 6-litre reactor keptunder a nitrogen atmosphere and protected from moisture.

165 ml (2.16 mol) of thionyl chloride are added dropwise to thissolution kept at room temperature. The reaction medium gradually becomesdark red. At the end of the addition, the reaction medium is stirred forminutes. After evaporation of the solvent, the residue is dissolved indiethyl ether. The organic solution is washed with water until a pH ofthe washings equal to 7 is obtained, and then dried over sodium sulfate.After evaporation of the solvent, 291.2 g of an oil are obtained, thatis to say a yield of about 100%.

Step 4

2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetonitrile.

58.2 g (1.186 mol) of sodium cyanide in suspension in 1.36 litres ofdimethyl sulfoxide are placed in a 6-litre reactor kept under a nitrogenatmosphere and protected from moisture. 291.2 g (1.13 mol) of thecompound obtained in the preceding step in solution in 1.2 litres ofdimethyl sulfoxide are added dropwise to this solution kept at roomtemperature. At the end of the addition, the reaction medium is stirredfor 48 hours. The solution is poured into an ice-water mixture. Theprecipitate formed is extracted three times with methylene chloride. Theorganic solution is washed with water and then dried over sodiumsulfate. After evaporation of the solvent, 262 g of an oil are obtained.This oil is dissolved in a methylene chloride-heptane: 1-1 mixture andis chromatographed on a silica gel. After evaporation of the solvent,196.7 g of an oil are obtained, that is to say a yield of 70.5%.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-3); Rf=0.63;I.R.: υ CN=2247 cm⁻¹; NMR: (CDCl₃): 3.1 (s, 2H); 5.0 (s, 2H); 6.65 (dd,1H); 6.8 (dd, 1H); 6.9 (dd, 1H); 7.15-7.3 (m, 3H); 7.4-7.6 (m, 3H).

Step 5

2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetic acid.

56.7 g (0.229 mol) of the compound obtained in the preceding step insolution in a mixture of 300 ml of acetic acid and 300 ml of aconcentrated hydrochloric acid solution are heated under reflux for 3hours in a 2-litre reactor. After cooling (standing for 12 hours at roomtemperature), a precipitate forms. After draining and rinsing withwater, the precipitate is solubilized in methylene chloride. The organicphase is washed with water (until a pH of the washings equal to 7 isobtained), dried over sodium sulfate and evaporated off. The solidobtained is dispersed in pentane and then drained. 54 g of the expectedproduct are thus obtained, that is to say a yield of 88%. This compoundhas a melting point of between 147 and 149° C.

I.R.: υ CO=1721 cm⁻¹; NMR: (CDCl₃): 3.1 (s, 2H); 4.8 (s, 2H); 6.6-7.3(m, 10H).

2—Other compounds of formula II in which Z is —CHR₉—.

By applying the operating protocol described above for the preparationof 2-(4-phenyl-2H-3-benzo[b]-pyranyl)acetic acid, the compoundsassembled in Table 3 below are prepared.

TABLE 3

Preparation Melting point No. X R₃ (° C.) III.2.1 O 4-F—C₆H₄— oilIII.2.2 CH₂ C₆H₅— oil

These compounds were obtained via the intermediates of Tables 4 to 7below.

TABLE 4

Intermediate Melting point No. X R₃ (° C.) VII.1 O 4-F—C₆H₄— 113-115VII.2 CH₂ C₆H₅— oil

More precisely, these compounds are prepared by carrying out theprocedure as in step 1 of § III.1 above from the appropriate reagents.

TABLE 5

Intermediate Melting point No. X R₃ (° C.) VI.1 O 4-F—C₆H₄— 96-98 VI.2CH₂ C₆H₅— oil

More precisely, these compounds were prepared by carrying out theprocedure as in step 2 of § III.1 above from the appropriate reagents.

TABLE 6

Intermediate Melting point No. X R₃ (° C.) V.1 O 4-F—C₆H₄— oil V.2 CH₂C₆H₅— oil

More precisely, these compounds were prepared by carrying out theprocedure as in step 3 of § III.1 above from the appropriate reagents.

TABLE 7

Intermediate Melting point No. X R₃ (° C.) IV.1 O 4-F—C₆H₄— oil IV.2 CH₂C₆H₅— oil

More precisely, these compounds were prepared by carrying out theprocedure as in step 4 of § III.1 above from the appropriate reagents.

EXAMPLE 1

N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-2-(4-phenyl-2H-3-benzo[b]pyranyl)acetamide.

45 g (0.169 mol) of 2-(4-phenyl-2H-3-benzo[b]pyranyl)acetic acid and23.5 ml (0.169 mol) of triethylamine in solution in 338 ml of methylenechloride are placed in a 2-litre reactor protected from moisture. 43.02g (0.169 mol) of bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride areadded in small portions to this solution kept between 0 and 5° C.,following which the reaction mixture is stirred for 1 h. 33.84 g (0.169mol) of 2,4-dimethylthio-6-methyl-3-pyridylamine are then added all atonce. 23.5 ml (0.169 mol) of triethylamine in solution in 68 ml ofmethylene chloride are then poured dropwise into this solution keptbetween 0 and 5° C., over a period of one hour. The reaction medium isgradually solubilized and is stirred for 12 hours at room temperature.After the addition of water and methylene chloride, a precipitate isfiltered and discarded. The reaction medium is allowed to separate outby settling and then the organic phase is washed with water and thenwith a hydrochloric acid solution and finally with water until a pH ofthe washings equal to 7 is obtained. After drying over sodium sulfate,the organic phase is evaporated off. The solid obtained is dispersed for30 minutes in 300 ml of ethanol and then drained. 52 g of the expectedproduct are obtained (in a wet state). The product is thenrecrystallized from 4.5 litres of ethanol and placed for 12 hours at−20° C. After draining, the solid obtained is dried in a ventilated oven(2 hours 30 minutes at 50-55° C.) and then for 20 hours at 95° C. 30.5 gof the expected compound are thus obtained, that is to say a yield of40.2%. This compound has a melting point of between 201-203° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-1); Rf=0.51;I.R.: υ NH=3198 cm⁻¹; CO=1661 cm⁻¹; NMR: (CDCl₃): 2.3 (sd, 3H); 2.4 (s,3H); 2.8-3.1 (sd, 2H); 4.8-5.0 (sd, 2H); 6.2-7.4 (m, 11H). Percentageanalysis: C₂₅H₂₄N₂O₂S₂ MW=448.5.

C H N S Calculated % 66.94 5.39 6.25 14.29 Found % 66.65 5.34 6.23 14.07

EXAMPLE 2

N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-3-(4-phenyl-2H-3-benzo[b]pyranyl)prop-2-enamide

1 g (3.59 mmol) of 3-(4-phenyl-2H-3-benzo[b]-pyranyl)prop-2-enoic acidin solution in 30 ml of methylene chloride is placed in a 250-ml reactorprotected from moisture, and a drop of dimethyl-formamide is addedthereto. 0.39 ml (3.76 mmol) of oxalyl chloride is poured dropwise intothis solution kept at room temperature. The reaction medium is thenheated under reflux for 1 hour. After evaporation of the solvent, thereaction medium is taken up in 20 ml of methylene chloride. Thissolution is then poured into a mixture kept between 0 and 5° C.consisting of 0.75 g (3.76 mmol) of2,4-dimethylthio-6-methyl-3-pyridylamine, 2.2 ml of pyridine and 30 mlof methylene chloride. The resulting reaction medium is stirred at roomtemperature for 12 hours. After addition of water, the organic phase isseparated after settling out, washed with a 2 normal hydrochloric acidsolution and then with water until a pH of the washings equal to 7 isobtained. After drying over sodium sulfate, the organic phase isevaporated off. The resulting solid is dispersed in 10 ml of hexane anddrained. 1.1 g of the expected compound are thus obtained in the crudestate. The latter is recrystallized from 140 ml of ethanol (12 hours at−20° C.) and then drained and dried. 0.77 g of the expected compound isobtained, that is to say a yield of 46.7%. ′This compound has a meltingpoint of between 225 and 227° C.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-1); Rf=0.59;I.R.: υ NH=3253, CO=1652; NMR: (CDCl₃): 2.35 (s, 3H); 2.4 (s, 3H); 2.45(s, 3H); 4.7 (s, 1H); 5.0 (s, 1H); 5.9-5.95 (d, 1H); 6.25 (s, 1H); 6.58(d, 1H); 6.62-6.80 (m, 2H); 6.84-6.87 (d, 1H); 7.05-7.17 (m, 3H);7.3-7.4 (m, 4H). Percentage analysis: C₂₆H₂₄N₂O₂S₂ MW 460.62.

C H N S Calculated % 67.80 5.25 6.08 13.92 Found % 67.54 5.25 6.15 14.15

The compounds of Examples 3 to 5 below were prepared according to theprocedure set out in Example 1, from appropriate reagents.

The compounds of Examples 6 to 15 below, for their part, were preparedon the model of the procedure of Example 2 from appropriate reagents.

These compounds are assembled in Tables 8 and 9 below.

TABLE 8

Melting point Ex. X R₁ R₂ R₃ R₆ + R₇ R₉ Ar (° C.) 3 O H H

Bond H

184-186 4 CH₂ H H

Bond H

218-220 5 O H H

Bond H

127-130 6 O H H

Bond H

234-236 7 O H H

Bond —C₄H₉

117-119 8 O H H

Bond H

250-253

TABLE 9

R₆ + R₇ R₁₀ + R₁₁ Melting or or point Ex. X R₁ R₂ R₃ R6, R7 R10, R11 Ar(° C.) 9 S H H

bond bond

215-217 10 O —(CH₂)₄—

bond bond

215-217 11 O —(CH₂)₄—

bond H, H

214-217 12 S H H

bond H, H

170-172 13 O H H

H, H H, H

166-168 14 S H H

bond Bond

248-250 15 S H H

bond H, H

194-196

In these two tables, “bond” means that R₆ and R₇, respectively R₁₀ andR₁₁, together form a bond.

EXAMPLE 16 2-(4-Phenyl-2H-3-benzo[b]pyranyl)hexanoic acid

3.1 ml (22 mmol) of diisopropylamine in solution in 20 ml oftetrahydrofuran are placed in a 250-ml reactor protected from moisture,and then 13.75 ml (22 mmol) of n-butyllithium in hexane (1.6 M) areadded dropwise to this solution kept at 0° C. After stirring thereaction medium for 15 minutes at 0° C., 2.66 g (10 mmol) of2-(4-phenyl-2H-3-benzo[b]-pyranyl)acetic acid are added dropwise to thissolution kept at 0° C. The reaction medium is stirred for 2 hours at 0°C. and then 1.18 ml (11 mmol) of 1-bromobutane are poured into thissolution kept at this temperature of 0° C. The reaction mixture isstirred for 72 hours at room temperature. After addition of water andhydrochloric acid (2 M), the reaction mixture is extracted with diethylether. The organic phase, after washing with water, is dried and thenevaporated off. The oil obtained is chromatographed on a silica gel(eluent: methylene chloride). After evaporation of the solvent, thecrystals obtained are dispersed in pentane and then drained. 1.7 g ofthe expected compound are thus obtained, that is to say a yield of52.8%. This compound has a melting point of between 117 and 119° C.

TLC (MERCK “Kieselgel 60” silica gel; AcOEt-hexane: 1-1); Rf=0.5; I.R.:υ CO=1697.

EXAMPLE 17

N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-enamide

Step 1

4-(4-Phenyl-2H-3-benzo[b]pyranyl)but-2-en-1-oic acid

1.9 g (0.008 mol) of 4-phenyl-2H-3-benzo[b]pyranylcarboxaldehyde and 3.5g (0.0084 mol) of 1-carboxypropylphosphonium bromide in suspension in 20ml of tetrahydrofuran are placed in a reactor kept protected frommoisture. A solution of 1.9 g (0.0176 mol) of potassium tert-butoxide in10 ml of tetrahydrofuran is added to this suspension over 1 hour at 0°C. The reaction medium is stirred for 30 minutes between 0 and 5° C. andthen for 1 hour at room temperature. The reaction medium is then pouredinto an ice-water mixture and then extracted with diethyl ether.

The aqueous phase is acidified with concentrated hydrochloric acid(pH=2). After extraction of the aqueous phase with ethyl acetate, theorganic phase is dried over sodium sulfate and evaporated. 2 g of asolid are obtained, which solid is dissolved in a methylenechloride-ethyl acetate: 9-1 mixture and is chromatographed on a silicagel. After evaporation of the solvent, 0.7 g of solid is obtained, thatis to say a yield of 29.9%.

TLC: (MERCK “Kieselgel 60” silica gel; AcOEt-CH₂Cl₂—MeOH: 45-45-10);Rf=0.65; I.R. γCO₂H=1718 cm⁻¹.

Step 2

N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-enamideis prepared under the conditions of Example 1 from4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-en-1-oic acid and2,4-dimethylthio-6-methyl-3-pyridylamine.

Melting point=204-206° C. TLC: (MERCK “Kieselgel 60” silica gel;AcOEt-hexane: 1-1; Rf=0.6); I.R.: γNH=3203 cm⁻¹; γCO=1651 cm⁻¹; NMR:(CDCl₃): 2.4 (s, 3H); 2.55 (s, 6H); 2.9-3.2 (m, 2H); 5.05-5.15 (m, 2H);5.9 (m, 1H); 6.3 (d, 1H); 6.6-7.5 (m, 11H).

What is claimed is:
 1. A compound of formula I

in which X is O or S; R₁ and R₂, which may be identical or different,are hydrogen, (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or alternatively R₁ andR₂, together with the carbon atom bearing them, form (C₃-C₈)cycloalkyl;R₃ is a (C₆-C₁₂)aryl optionally substituted with one or more Y radicals,which may be identical or different; Y is halogen, a (C₁-C₆)alkyloptionally substituted with one or more halogens, a (C₁-C₆)alkoxyoptionally substituted with one or more halogens, a (C₁-C₆)alkylthiooptionally substituted with one or more halogens, (C₁-C₇)acylamino,(C₁-C₃)acyloxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, pyrrolidono, piperidino, morpholino,(C₁-C₄)alkylsulfonylamino, (C₂-C₅)alkoxycarbonyl, carboxyl,(C₂-C₆)alkylcarbonyl, carbamoyl, (C₂-C₅)alkylcarbamoyl,di-(C₂-C₅)alkylcarbamoyl or (C₁-C₆)alkyl-sulfonyl; R₄ and R₅, which maybe identical or different, are a Y radical or alternatively a hydrogenatom; Ar is one of the following groups B or C:

T₁ and T₂, which may be identical or different, are halogen,(C₁-C₆)alkoxy, (C₁-C₆)alkylthio or (C₁-C₆)alkyl; T is a hydrogen atom or(C₁-C₆)alkyl; T₃ and T₄, which may be identical or different, are(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkylthio, (C₆-C₁₂)arylthio,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylcarbonyl, (C₆-C₁₂)arylcarbonyl or—(CH₂)_(p)—OR in which p is 1, 2, 3 or 4 and R is (C₂-C₃)alkyl, R₆ andR₇ are each a hydrogen atom or alternatively R₆ and R₇ together are abond; Z is either (i) the divalent group —CHR₉— in which R₉ is ahydrogen atom or (C₁-C₆)alkyl; or (ii) the divalent group —CHR₁₀—CHR₁₁—in which R₁₀ and R₁₁ together form a bond such that Z is —CH═CH— oralternatively R₁₀ and R₁₁, which may be identical or different, are asdefined above for R₉; or (iii) the divalent group —CHR₁₂—CHR₁₃—CH₂— inwhich R₁₂ and R₁₃ together form a bond such that Z is —CH═CH—CH₂—, oralternatively R₁₂ and R₁₃, which may be identical or different, are asdefined above for R₉, as well as its addition salts with apharmaceutically acceptable acid or base.
 2. A compound according toclaim 1, wherein Y is halogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy ortrifluoromethyl.
 3. A compound according to claim 1, wherein: R₁ and R₂,which may be identical or different, are hydrogen or alternatively R₁and R₂, together with the carbon atom bearing them, form(C₃-C₈)cycloalkyl; R₃ is a (C₆-C₁₂)aryl optionally substituted with oneor more Y radicals, which may be identical or different; Y is halogen;R₄ and R₅ are each a hydrogen atom; Ar is one of the following groups Bor C:

T₁ and T₂, which may be identical or different, are (C₁-C₆)alkyl; T is ahydrogen atom or (C₁-C₆)alkyl; T₃ and T₄, which may be identical ordifferent, are (C₁-C₆)alkyl; (C₁-C₆)alkoxy or (C₁-C₆)alkylthio; R₆ andR₇ are each a hydrogen atom or alternatively R₆ and R₇ together are abond; Z is either (i) the divalent group —CHR₉— in which R₉ is ahydrogen atom or (C₁-C₆)alkyl; or (ii) the divalent group —CHR₁₀—CHR₁₁—in which R₁₀ and R₁₁ together form a bond such that Z is —CH═CH—, oralternatively R₁₀ and R₁₁ are each a hydrogen atom.
 4. A compoundaccording to claim 1, wherein R₁ and R₂ are a hydrogen atom.
 5. Acompound according to claim 1 wherein Z is —CHR₁₂—CHR₁₃—CH₂.
 6. Acompound according to claim 1, wherein X is O or S and R₁ and R₂,together with the carbon atom bearing them, form a (C₃-C₈)cycloalkyl. 7.A compound according to claim 1 wherein X is O or S and Z is chosenfrom: (i) —CH═CH—, and (ii) —CH═CH—CH₂—.
 8. A compound according toclaim 1, wherein Ar is chosen from 2,4-dimethylthio-6-methyl-3-pyridyl;and 2-methoxy-4-hexylthio-3-pyridyl.
 9. A method of preparing a compoundof formula I according to claim 1, which comprises coupling an acid offormula II, in activated form,

in which R₁, R₂, R₃, R₄, R₅, R₆, R₇ and Z are as defined in claim 1,with an aromatic amine of formula III: Ar—NH₂  (III) in which Ar is asdefined in claim
 1. 10. A method according to claim 9, wherein thecoupling of the compound of formula II and of the amine III comprises:(i) activating the acid of formula II by formation of an acid chloride,of an ester or of a mixed anhydride thereof; and (ii) reacting the amineof formula III with the compound resulting from step (i).
 11. A methodaccording to claim 9, which comprises: (i) treating an acid of formulaII with bis(2-oxo-3-oxazolidinyl)phosphinic acid in the presence of abase; and then (ii) reacting an amine of formula III with the compoundobtained in step (i).
 12. A method according to claim 9, whichcomprises: (i) treating an acid of formula II with oxalyl chloride inthe presence of dimethylformamide; and then (ii) reacting an amine offormula III with the compound obtained in step (i).
 13. A pharmaceuticalcomposition comprising at least one compound according to claim 1, asactive ingredient in combination with one or more pharmaceuticallyacceptable vehicles.
 14. A pharmaceutical composition of claim 13 whichexhibits a hypolipidemic or anti-atherosclerotic activity, is in theform of an assay unit, and contains 10 mg to 500 mg of active ingredientmixed with a pharmaceutically acceptable excipient.
 15. A methodcomprising administering to a patient a compound according to claim 1for the treatment of hyperlipidemia.
 16. A method comprisingadministering to a patient a compound according to claim 1 for thetreatment of atherosclerosis.
 17. A compound of formula I according toclaim 1

in which X is O, R₁ and R₂, which may be identical or different, arehydrogen, (C₁-C₆)alkyl or (C₃-C₈)cycloalkyl, or alternatively R₁ and R₂,together with the carbon atom bearing them, form (C₃-C₈)cycloalkyl; R₃is a (C₆-C₂)aryl optionally substituted with one or more Y radicals,which may be identical or different; Y is halogen, a (C₁-C₆)alkyloptionally substituted with one or more halogens, a (C₁-C₆)alkoxyoptionally substituted with one or more halogens, a (C₁-C₆) alkylthiooptionally substituted with one or more halogenis, (C₁-C₇)acylamino,(C₁-C₃)acyloxy, hydroxyl, nitro, cyano, amino, (C₁-C₆)alkylamino,di-(C₁-C₆)alkylamino, pyrrolidono, peperidino maperidino, morpholino,(C₁-C₄)alkylsulfonylamino, (C₂-C₅)alkoxycarbonyl, carboxyl,(C₂-C₆)alkylcarbonyl, carbamoyl, (C₂-C₅)alkylcarbamoyl,di-(C₂-C₅)alkylcarbamoyl or (C₁-C₆))alkylsufonyl; R₄ and R₅, which maybe identical or different, are a Y radical or alternatively a hydrogenatom; Ar is:

T is a hydrogen atom or (C₁-C₆)alkyl; T₃ and T₄, which may be identicalor different, are (C₁-C₆)alkylthio; R₆ and R₇ are each a hydrogen atomor alternatively R₆ an d R₇ together are a bond; Z is either (i) thedivalent group —CHR₉— in which R₉ is a hydrogen atom or (C₁-C₆)alkyl; or(ii) the divalent group —CHR₁₀—CHR₁₁— in which R₁₀ and R₁₁ together forma bond such that Z is —CH═CH— or alternatively R₁₀ and R₁₁, which may beidentical or different, are as defined above for R₉; or (iii) thedivalent group —CHR₁₂—CHR₁₃—CH₂— in which R₁₂ and R₁₃ together form abond such that Z is —CH═CH—CH₂—, or alternatively R₁₂ and R₁₃, which maybe identical or different, are as defined above for R₉, as well as itsaddition salts with a pharmaceutically acceptable acid or base.